Open AccessKlotho‐mediated targeting of CCL 2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments
Author(s) -
Liu Yangyang,
Pan Jie,
Pan Xia,
Wu Lunpo,
Bian Jun,
Lin Zhenghua,
Xue Meng,
Su Tingting,
Lai Sanchuan,
Chen Fei,
Ge Qiwei,
Chen Luyi,
Ye Shufang,
Zhu Yabi,
Chen Shujie,
Wang Liangjing
Publication year - 2019
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12577
Subject(s) - stromal cell , cancer research , senescence , klotho , downregulation and upregulation , cell growth , biology , cell , tumor progression , cancer , microbiology and biotechnology , medicine , endocrinology , gene , biochemistry , genetics , kidney
Senescent microenvironments play an important role in tumor progression. Here, we report that doxorubicin ( DOX )‐pretreated or replicative senescent stromal cells ( WI ‐38 and HUVEC ) promote colorectal cancer ( CRC ) cell growth and invasion in vitro and in vivo . These pro‐tumorigenic effects were attenuated by exogenous administration of Klotho, an anti‐aging factor. We subsequently identified several senescence‐associated secretory phenotype ( SASP )‐associated genes, including CCL 2, which were significantly upregulated in both types of senescent stromal cells during replication and DNA damage‐induced senescence. Importantly, we found that the secretion of CCL 2 by senescent stromal cells was significantly higher than that seen in nonsenescent cells or in senescent cells pretreated with Klotho. Notably, CCL 2 was found to accelerate CRC cell proliferation and invasion, while this effect could be blocked by administration of a specific CCR 2 antagonist. We further show that Klotho can suppress NF ‐κB activation during DOX ‐induced senescence and thus block CCL 2 transcription. Low expression of Klotho, or high expression of CCL 2 in patient tumor tissues, correlated with poor overall survival of CRC patients. Collectively, our findings suggest that senescent stromal cells are linked to progression of CRC . Klotho can suppress the senescent stromal cell‐associated triggering of CRC progression by inhibiting the expression of SASP factors including CCL 2. The identification of key SASP factors such as CCL 2 may provide potential therapeutic targets for improving CRC therapy.